In order to understand the biochemical basis of morphine tolerance and physical dependence mechanism, the contributory role of the putative neurotransmitters in the brain will be assessed. The approach will be to alter the functional state of acetylcholine, dopamine, norepinephrine, serotonin, cyclic AMP and GABA with agents which might affect their synthesis, storage, uptake, release and degradation. Insofar as possible, only one brain substance will be manipulated at a time but in order to study their physiologic balance, it may be necessary to sometimes modify the state of two or more neurohormones simultaneously. Attempts will be made to implicate the neurohormone involved in mediating morphine effects and in the withdrawal syndrome.